Publications by authors named "Beatrice Arosio"

95 Publications

Whole-genome sequencing analysis of semi-supercentenarians.

Elife 2021 May 4;10. Epub 2021 May 4.

Department of Medicine, Unit of Internal Medicine, University of Verona, Verona, Italy.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.
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http://dx.doi.org/10.7554/eLife.57849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096429PMC
May 2021

Anti-Inflammatory Effects of Fatty Acid Amide Hydrolase Inhibition in Monocytes/Macrophages from Alzheimer's Disease Patients.

Biomolecules 2021 Mar 26;11(4). Epub 2021 Mar 26.

Laboratory of Neurochemistry of Lipids, European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, 00143 Rome, Italy.

Growing evidence shows that the immune system is critically involved in Alzheimer's disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannabinoid (eCB) system in modulating immune functions, we investigated the potential role of the main elements of such a system, namely type-1 and type-2 cannabinoid receptors (CB and CB), and fatty acid amide hydrolase (FAAH), in distinct immune cell populations of the peripheral blood of AD patients. We found that, compared to healthy controls, CB and CB expression was significantly lower in the B-lymphocytes of AD patients. Moreover, we found that CB was significantly lower and FAAH was significantly higher in monocytes of the same subjects. In contrast, T-lymphocytes and NK cells did not show any variation in any of these proteins. Of note, monocytic CB and FAAH levels significantly correlated with clinical scores. Furthermore, the pharmacological inactivation of FAAH in monocytes and monocyte-derived macrophages obtained from AD patients was able to modulate their immune responses, by reducing production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12, and enhancing that of the anti-inflammatory cytokine IL-10. Furthermore, FAAH blockade skewed AD monocyte-derived macrophages towards a more anti-inflammatory and pro-resolving phenotype. Collectively, our findings highlight a central role of FAAH in regulating AD monocytes/macrophages that could be of value in developing novel monocyte-centered therapeutic approaches aimed at promoting a neuroprotective environment.
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http://dx.doi.org/10.3390/biom11040502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066292PMC
March 2021

Hypothetical COVID-19 protection mechanism: hints from centenarians.

Immun Ageing 2021 Mar 30;18(1):15. Epub 2021 Mar 30.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

The risk of serious complications and the fatality rate due to COVID-19 pandemic have proven particularly higher in older persons, putting a further strain in healthcare system as we dramatically observed.COVID-19 is not exclusively gerophile (géro "old" and philia "love") as young people can be infected, even if older people experience more severe symptoms and mortality due to their greater frailty. Indeed, frailty could complicate the course of COVID-19, much more than the number of years lived. As demonstration, there are centenarians showing remarkable capacity to recover after coronavirus infection.We hypothesize that centenarian's portfolio could help in identifying protective biological mechanisms underlying the coronavirus infection.The human leukocyte antigen (HLA) is one of the major genetic regions associated with human longevity, due to its central role in the development of adaptive immune response and modulation of the individual's response to life threatening diseases. The HLA locus seems to be crucial in influencing susceptibility and severity of COVID-19.In this hypothesis, we assume that the biological process in which HLA are involved may explain some aspects of coronavirus infection in centenarians, although we cannot rule out other biological mechanisms that these extraordinary persons are able to adopt to cope with the infection.
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http://dx.doi.org/10.1186/s12979-021-00226-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008020PMC
March 2021

The sTREM2 Concentrations in the Blood: A Marker of Neurodegeneration?

Front Mol Biosci 2020 9;7:627931. Epub 2021 Mar 9.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Microglia performs a variety of functions during brain development designed to maintain brain homeostasis. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in microglial cells modulating phagocytosis, cytokine production, cell proliferation, and cell survival. Interestingly, the levels of soluble TREM2 (the secreted ectodomain of TREM2, sTREM2) were higher in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients than subjects without cognitive decline. It is noteworthy that, while CSF sTREM2 levels have been extensively studied, few studies have investigated sTREM2 in blood producing conflicting results. We aimed to investigate the levels of sTREM2 in CSF and blood from a cohort of well-characterized AD comparing the results to those obtained in patients suffering from idiopathic normal pressure hydrocephalus (iNPH), a potentially reversible cognitive impairment. Our findings underlined a significantly lower plasma sTREM2 concentration in AD patients compared to iNPH subjects [39.1 ng/mL (standard deviation (SD), 15.0) and 47.2 ng/mL (SD, 19.5), respectively; = 0.01], whereas no difference was revealed between the two groups in the CSF sTREM2 levels. The adjusted regression analyses evidenced in AD patients an association between plasma and CSF sTREM2 levels [ = 0.411; 95% confidence interval (CI), 0.137-0.685, = 0.004], as well as β-amyloid concentrations ( = 0.035; 95% CI, 0.007-0.063, = 0.01) and an association between CSF sTREM2 and phospho-Tau concentrations ( = 0.248; 95% CI, 0.053-0.443; = 0.01). No significant relation was found in iNPH patients. In conclusion, these differences in sTREM2 profiles between AD and iNPH reinforce the notion that this receptor has a role in neurodegeneration.
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http://dx.doi.org/10.3389/fmolb.2020.627931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985346PMC
March 2021

Nutrition and Muscle Health.

Nutrients 2021 Feb 28;13(3). Epub 2021 Feb 28.

Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.

The increase in human life expectancy at birth and the rapid aging of the population represent major social phenomena of this time.[...].
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http://dx.doi.org/10.3390/nu13030797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997193PMC
February 2021

Blood Brain-Derived Neurotrophic Factor (BDNF) and Major Depression: Do We Have a Translational Perspective?

Front Behav Neurosci 2021 12;15:626906. Epub 2021 Feb 12.

Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Major depressive disorder (MDD) affects millions of people worldwide and is a leading cause of disability. Several theories have been proposed to explain its pathological mechanisms, and the "neurotrophin hypothesis of depression" involves one of the most relevant pathways. Brain-derived neurotrophic factor (BDNF) is an important neurotrophin, and it has been extensively investigated in both experimental models and clinical studies of MDD. Robust empirical findings have indicated an association between increased BDNF gene expression and peripheral concentration with improved neuronal plasticity and neurogenesis. Additionally, several studies have indicated the blunt expression of BDNF in carriers of the Val66Met gene polymorphism and lower blood BDNF (serum or plasma) levels in depressed individuals. Clinical trials have yielded mixed results with different treatment options, peripheral blood BDNF measurement techniques, and time of observation. Previous meta-analyses of MDD treatment have indicated that antidepressants and electroconvulsive therapy showed higher levels of blood BDNF after treatment but not with physical exercise, psychotherapy, or direct current stimulation. Moreover, the rapid-acting antidepressant ketamine has presented an early increase in blood BDNF concentration. Although evidence has pointed to increased levels of BDNF after antidepressant therapy, several factors, such as heterogeneous results, low sample size, publication bias, and different BDNF measurements (serum or plasma), pose a challenge in the interpretation of the relation between peripheral blood BDNF and MDD. These potential gaps in the literature have not been properly addressed in previous narrative reviews. In this review, current evidence regarding BDNF function, genetics and epigenetics, expression, and results from clinical trials is summarized, putting the literature into a translational perspective on MDD. In general, blood BDNF cannot be recommended for use as a biomarker in clinical practice. Moreover, future studies should expand the evidence with larger samples, use the serum or serum: whole blood concentration of BDNF as a more accurate measure of peripheral BDNF, and compare its change upon different treatment modalities of MDD.
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http://dx.doi.org/10.3389/fnbeh.2021.626906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906965PMC
February 2021

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.

Pharmacol Res 2021 Feb 4;164:105357. Epub 2020 Dec 4.

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic. Electronic address:

Perinatal exposure to Δ-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
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http://dx.doi.org/10.1016/j.phrs.2020.105357DOI Listing
February 2021

Can Serum Nitrosoproteome Predict Longevity of Aged Women?

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Department of Biomedical Sciences for Health, University of Milan, 20090 Segrate, Italy.

Aging is characterized by increase in reactive oxygen (ROS) and nitrogen (RNS) species, key factors of cardiac failure and disuse-induced muscle atrophy. This study focused on serum nitroproteome as a trait of longevity by adopting two complementary gel-based techniques: two-dimensional differential in gel electrophoresis (2-D DIGE) and Nitro-DIGE coupled with mass spectrometry of albumin-depleted serum of aged (A, = 15) and centenarian (C, = 15) versus young females (Y, = 15). Results indicate spots differently expressed in A and C compared to Y and spots changed in A vs. C. Nitro-DIGE revealed nitrosated protein spots in A and C compared to Y and spots changed in A vs. C only (-value < 0.01). Nitro-proteoforms of alpha-1-antitripsin (SERPINA1), alpha-1-antichimotripsin (SERPINA3), ceruloplasmin (CP), 13 proteoforms of haptoglobin (HP), and inactive glycosyltransferase 25 family member 3 (CERCAM) increased in A vs. Y and C. Conversely, nitrosation levels decreased in C vs. Y and A, for immunoglobulin light chain 1 (IGLC1), serotransferrin (TF), transthyretin (TTR), and vitamin D-binding protein (VDBP). Immunoblottings of alcohol dehydrogenase 5/S-nitrosoglutathione reductase (ADH5/GSNOR) and thioredoxin reductase 1 (TRXR1) indicated lower levels of ADH5 in A vs. Y and C, whereas TRXR1 decreased in A and C in comparison to Y. In conclusion, the study identified putative markers in C of healthy aging and high levels of ADH5/GSNOR that can sustain the denitrosylase activity, promoting longevity.
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http://dx.doi.org/10.3390/ijms21239009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731247PMC
November 2020

Corrigendum to "Peripheral Blood Mononuclear Cells as a Laboratory to Study Dementia in the Elderly".

Biomed Res Int 2020 7;2020:9175369. Epub 2020 Sep 7.

Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy.

[This corrects the article DOI: 10.1155/2014/169203.].
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http://dx.doi.org/10.1155/2020/9175369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505014PMC
September 2020

Vitamin D Receptor Polymorphisms in Sex-Frailty Paradox.

Nutrients 2020 Sep 5;12(9). Epub 2020 Sep 5.

Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.

The "male-female health-survival paradox" evidences that the survival advantage observed in women is linked to higher rates of disability and poor health status compared to men, a phenomenon also called the "sex-frailty paradox". The depletion of vitamin D seems to play a role in the fragilization of old persons, and genetic polymorphisms of the () gene seem to be involved in regulating the vitamin D pathway. This study correlated the gene polymorphisms (FokI, ApaI, BsmiI, and TaqI) with frailty, computed by frailty index (FI), in 202 persons (127 women and 75 men, aged from 60 to 116 years), aiming to capture the involvement of vitamin D in the sex-frailty paradox. The results showed slightly higher FI ( = 0.05), lower levels of 25(OH)D ( = 0.04), and higher levels of parathyroid hormone PTH ( = 0.002) and phosphorus ( < 0.001) in women than in men. Interestingly, the ApaI minor allele (Aa + aa) showed a significant positive association with FI ( = 0.03) and a negative association with inorganic phosphorus values ( = 0.04) compared to AA genotype only in women, regardless of age. The exact mechanism and the causal role that, in old women, links ApaI polymorphism with frailty are still unclear. However, we could speculate that a specific genetic profiling, other than 25(OH)D levels, play a role in the sex-frailty paradox.
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http://dx.doi.org/10.3390/nu12092714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551757PMC
September 2020

Role of Age-Related Mitochondrial Dysfunction in Sarcopenia.

Int J Mol Sci 2020 Jul 23;21(15). Epub 2020 Jul 23.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.
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http://dx.doi.org/10.3390/ijms21155236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432902PMC
July 2020

Prothrombin is a binding partner of the human receptor of advanced glycation end products.

J Biol Chem 2020 08 14;295(35):12498-12511. Epub 2020 Jul 14.

Department of Biosciences, University of Milan, Milan, Italy

The receptor for advanced glycation end products (RAGE) plays a key role in mammal physiology and in the etiology and progression of inflammatory and oxidative stress-based diseases. In adults, RAGE expression is normally high only in the lung where the protein concentrates in the basal membrane of alveolar Type I epithelial cells. In diseases, RAGE levels increase in the affected tissues and sustain chronic inflammation. RAGE exists as a membrane glycoprotein with an ectodomain, a transmembrane helix, and a short carboxyl-terminal tail, or as a soluble ectodomain that acts as a decoy receptor (sRAGE). VC1 domain is responsible for binding to the majority of RAGE ligands including advanced glycation end products (AGEs), S100 proteins, and HMGB1. To ascertain whether other ligands exist, we analyzed by MS the material pulled down by VC1 from human plasma. Twenty of 295 identified proteins were selected and associated to coagulation and complement processes and to extracellular matrix. Four of them contained a γ-carboxyl glutamic acid (Gla) domain, a calcium-binding module, and prothrombin (PT) was the most abundant. Using MicroScale thermophoresis, we quantified the interaction of PT with VC1 and sRAGE in the absence or presence of calcium that acted as a competitor. PT devoid of the Gla domain (PT des-Gla) did not bind to sRAGE, providing further evidence that the Gla domain is critical for the interaction. Finally, the presence of VC1 delayed plasma clotting in a dose-dependent manner. We propose that RAGE is involved in modulating blood coagulation presumably in conditions of lung injury.
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http://dx.doi.org/10.1074/jbc.RA120.013692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458805PMC
August 2020

Author Correction: Particular CSF sphingolipid patterns identify iNPH and AD patients.

Sci Rep 2020 Jun 11;10(1):9724. Epub 2020 Jun 11.

Department of Biomedical Sciences for Health, University of Milan, Segrate, Milan, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-66184-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289802PMC
June 2020

Thyroid hormones and frailty in persons experiencing extreme longevity.

Exp Gerontol 2020 09 7;138:111000. Epub 2020 Jun 7.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Istituto Auxologico Italiano, IRCCS, Laboratorio Sperimentale di Ricerche di Neuroendocrinologia Geriatrica ed Oncologica, Cusano Milanino, Italy. Electronic address:

Context: The aging phenotype is quite heterogeneous, being the result of the capability of each individual to successfully or unsuccessfully response to stressors. The reduction of homeostatic reserve characterizing aging is accompanied by a remodeling of the endocrine system. Frailty has been indicated as a promising way for capturing the physiological decline as well as the biological aging of the individuals. In particular, the Frailty Index (FI), based on the assumption that health deficits tend to accumulate with aging, represents a quantitative measure of extreme interest.

Objective: The study aims to correlate the thyroid hormone levels with FI in a population of centenarians and their offspring to capture the effects of thyroid remodeling in extreme longevity.

Study Design: The study described 593 well-characterized Italian subjects, including 180 centenarians, as well as 276 centenarian's offspring and 137 age-matched controls.

Results: FT3 levels and FT3/FT4 ratio were significantly lower (p < 0.001) and TSH levels higher (p < 0.001) in centenarians compared to the other groups, analysing both overall subjects and excluding subjects with hormone levels out of the normal ranges. In overall centenarians, we observed a negative correlation between FI and FT3 (ρ: -0.281, p < 0.001), FT3/FT4 (ρ: -0.344, p < 0.001) and TSH (ρ: -0.223, p 0.003) and a positive association between FI and FT4 (ρ: 0.189, p = 0.001). In centenarians with hormone levels within the normal ranges, similar negative correlations were observed between FI and FT3 (ρ: -0.201, p = 0.02) and FT3/FT4 (ρ: -0.264, p = 0.002). In this sub-analysis, FI positively correlated with FT4 and age (ρ: 0.167, p = 0.05; ρ: 0.219, p = 0.005, respectively). Conversely, no significant correlations were observed between hormone levels and FI in offspring and controls.

Conclusions: We found an association between thyroid hormone levels and frailty in centenarians, underlying the significant role of thyroid in the aging process and longevity.
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http://dx.doi.org/10.1016/j.exger.2020.111000DOI Listing
September 2020

Genomic history of the Italian population recapitulates key evolutionary dynamics of both Continental and Southern Europeans.

BMC Biol 2020 05 22;18(1):51. Epub 2020 May 22.

Interdepartmental Centre Alma Mater Research Institute on Global Challenges and Climate Change, University of Bologna, Bologna, Italy.

Background: The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes.

Results: We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition.

Conclusions: We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes.
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http://dx.doi.org/10.1186/s12915-020-00778-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243322PMC
May 2020

Possible clinical anatomical features of right Alzheimer's disease (RAD).

Aging Clin Exp Res 2021 Mar 1;33(3):669-671. Epub 2020 May 1.

Geriatric Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1007/s40520-020-01564-6DOI Listing
March 2021

Editorial: Biomarkers to Disentangle the Physiological From Pathological Brain Aging.

Front Aging Neurosci 2020 15;12:88. Epub 2020 Apr 15.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.3389/fnagi.2020.00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174597PMC
April 2020

LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters.

Atherosclerosis 2020 03 31;297:8-15. Epub 2020 Jan 31.

Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address:

Background And Aims: Cholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function.

Methods: Lipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells.

Results: Despite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced. Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells.

Conclusions: LIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.01.026DOI Listing
March 2020

Nutritional Status as a Mediator of Fatigue and Its Underlying Mechanisms in Older People.

Nutrients 2020 Feb 10;12(2). Epub 2020 Feb 10.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Fatigue is an often-neglected symptom but frequently complained of by older people, leading to the inability to continue functioning at a normal level of activity. Fatigue is frequently associated with disease conditions and impacts health status and quality of life. Yet, fatigue cannot generally be completely explained as a consequence of a single disease or pathogenetic mechanism. Indeed, fatigue mirrors the exhaustion of the physiological reserves of an older individual. Despite its clinical relevance, fatigue is typically underestimated by healthcare professionals, mainly because reduced stamina is considered to be an unavoidable corollary of aging. The incomplete knowledge of pathophysiological mechanisms of fatigue and the lack of a gold standard tool for its assessment contribute to the poor appreciation of fatigue in clinical practice. Inadequate nutrition is invoked as one of the mechanisms underlying fatigue. Modifications in food intake and body composition changes seem to influence the perception of fatigue, probably through the mechanisms of inflammation and/or mitochondrial dysfunction. Here, we present an overview on the mechanisms that may mediate fatigue levels in old age, with a special focus on nutrition.
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http://dx.doi.org/10.3390/nu12020444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071235PMC
February 2020

Vitamin D in physiological and pathological aging: Lesson from centenarians.

Rev Endocr Metab Disord 2019 09;20(3):273-282

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Vitamin D is a secosteroid hormone that exerts a pleiotropic action on a wide spectrum of tissues, apparatuses and systems. Thus, vitamin D has assumed an increasingly dominant role as a key determinant of biological mechanisms and specific clinical conditions. Older people frequently present vitamin D deficiency, a status potentially influencing several mechanisms responsible for different age-related diseases. Centenarians symbolize the ideal model for investigating the peculiar traits of longevity, as they have reached an age close to the estimated limit of the human lifespan. Interestingly, despite the profound heterogeneity of centenarians in terms of health status, all these people share the same condition of severe vitamin D deficiency, suggesting that they may have implemented a number of adaptive strategies to cope with the age-related physiological derangement of vitamin D metabolism. The lesson deriving from centenarians' experience suggests that: i) severe vitamin D deficiency does not preclude the possibility of reaching extreme longevity, ii) strategies to prevent hypovitaminosis D may be useful to slow down the processes of "fragilization" occurring in aged people, iii) beneficial effects of vitamin D supplementation need to be confirmed regarding longevity.
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http://dx.doi.org/10.1007/s11154-019-09522-yDOI Listing
September 2019

Exosome Determinants of Physiological Aging and Age-Related Neurodegenerative Diseases.

Front Aging Neurosci 2019 28;11:232. Epub 2019 Aug 28.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Aging is consistently reported as the most important independent risk factor for neurodegenerative diseases. As life expectancy has significantly increased during the last decades, neurodegenerative diseases became one of the most critical public health problem in our society. The most investigated neurodegenerative diseases during aging are Alzheimer disease (AD), Frontotemporal Dementia (FTD) and Parkinson disease (PD). The search for biomarkers has been focused so far on cerebrospinal fluid (CSF) and blood. Recently, exosomes emerged as novel biological source with increasing interest for age-related neurodegenerative disease biomarkers. Exosomes are tiny Extracellular vesicles (EVs; 30-100 nm in size) released by all cell types which originate from the endosomal compartment. They constitute important vesicles for the release and transfer of multiple (signaling, toxic, and regulatory) molecules among cells. Initially considered with merely waste disposal function, instead exosomes have been recently recognized as fundamental mediators of intercellular communication. They can move from the site of release by diffusion and be retrieved in several body fluids, where they may dynamically reflect pathological changes of cells present in inaccessible sites such as the brain. Multiple evidence has implicated exosomes in age-associated neurodegenerative processes, which lead to cognitive impairment in later life. Critically, consolidated evidence indicates that pathological protein aggregates, including Aβ, tau, and α-synuclein are released from brain cells in association with exosomes. Importantly, exosomes act as vehicles between cells not only of proteins but also of nucleic acids [DNA, mRNA transcripts, miRNA, and non-coding RNAs (ncRNAs)] thus potentially influencing gene expression in target cells. In this framework, exosomes could contribute to elucidate the molecular mechanisms underneath neurodegenerative diseases and could represent a promising source of biomarkers. Despite the involvement of exosomes in age-associated neurodegeneration, the study of exosomes and their genetic cargo in physiological aging and in neurodegenerative diseases is still in its infancy. Here, we review, the current knowledge on protein and ncRNAs cargo of exosomes in normal aging and in age-related neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnagi.2019.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722391PMC
August 2019

Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution.

Genome Res 2019 11 23;29(11):1878-1888. Epub 2019 Sep 23.

Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.

Mitochondria are involved in a number of diverse cellular functions, including energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, and motility, as well as free radical generation. Mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner. mtDNA copy number also varies during aging and disease progression and therefore might be considered as a biomarker that mirrors alterations within the human body. Here, we present a new quantitative, highly sensitive droplet digital PCR (ddPCR) method, droplet digital mitochondrial DNA measurement (ddMDM), to measure mtDNA copy number not only from cell populations but also from single cells. Our developed assay can generate data in as little as 3 h, is optimized for 96-well plates, and also allows the direct use of cell lysates without the need for DNA purification or nuclear reference genes. We show that ddMDM is able to detect differences between samples whose mtDNA copy number was close enough as to be indistinguishable by other commonly used mtDNA quantitation methods. By utilizing ddMDM, we show quantitative changes in mtDNA content per cell across a wide variety of physiological contexts including cancer progression, cell cycle progression, human T cell activation, and human aging.
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http://dx.doi.org/10.1101/gr.250480.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836731PMC
November 2019

Efficacy of Nutritional Interventions as Stand-Alone or Synergistic Treatments with Exercise for the Management of Sarcopenia.

Nutrients 2019 Aug 23;11(9). Epub 2019 Aug 23.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Sarcopenia is an age-related and accelerated process characterized by a progressive loss of muscle mass and strength/function. It is a multifactorial process associated with several adverse outcomes including falls, frailty, functional decline, hospitalization, and mortality. Hence, sarcopenia represents a major public health problem and has become the focus of intense research. Unfortunately, no pharmacological treatments are yet available to prevent or treat this age-related condition. At present, the only strategies for the management of sarcopenia are mainly based on nutritional and physical exercise interventions. The purpose of this review is, thus, to provide an overview on the role of proteins and other key nutrients, alone or in combination with physical exercise, on muscle parameters.
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http://dx.doi.org/10.3390/nu11091991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770476PMC
August 2019

Does the Right Focal Variant of Alzheimer's Disease Really Exist? A Literature Analysis.

J Alzheimers Dis 2019 ;71(2):405-420

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Alzheimer's disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated.

Objective: To explore the existence of focal RAD on the basis of existing literature.

Methods: We performed a literature search for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD.

Results: Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome.

Conclusion: Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition.
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http://dx.doi.org/10.3233/JAD-190338DOI Listing
November 2020

The Frailty Index in centenarians and their offspring.

Aging Clin Exp Res 2019 Nov 29;31(11):1685-1688. Epub 2019 Jul 29.

Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Via Pace 9, 20122, Milan, Italy.

Frailty has been indicated as a way for capturing biological aging of the individual and Frailty Index (FI) may serve for this purpose. This study designed the FI in a cohort of centenarians, their offspring and control subjects sex- and age-matched with offspring. The FI mean value was 0.47 (SD 0.13) in centenarians, 0.15 (SD 0.12) in their offspring, and 0.22 (SD 0.14) in controls (p < 0.001). The difference between offspring and controls was statistically significant (p = 0.003). The correlation between FI and age was significant in offspring (r = 0.46, p < 0.001), close to significance in controls (r = 0.25, p = 0.08) and not significant in centenarians. Our study confirms that FI is a marker of biological age useful to discriminate different degrees of frailty even at extremely advanced age.
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http://dx.doi.org/10.1007/s40520-019-01283-7DOI Listing
November 2019

Gut microbiota and physical frailty through the mediation of sarcopenia.

Exp Gerontol 2019 09 18;124:110639. Epub 2019 Jun 18.

Geriatric Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Via Pace 9, 20122 Milan, Italy. Electronic address:

The changing physiology and lifestyle of older people affect the gut microbiota composition. In particular, the age-related diet modifications can alter the gut microbiota biodiversity and determine the relative abundance of specific microbial taxa, resulting in microbiota dysbiosis with negative consequences for the host physiology. Unhealthy microbiota may then induce an acceleration of the age-related physiological changes, consequently concurring at determining the characteristic complexity of frail older persons. One of the major clinical manifestations of frailty is represented by the individual's physical decline. Besides of a well-established clinical phenotype of frailty, the qualitative and quantitative skeletal muscle impairment (i.e., sarcopenia) is today of particular interest for potentially serving as target for (pharmacological and non-pharmacological) interventions to prevent incident disability. Evidence suggests that gut microbiota is able to influence the skeletal muscle homeostasis via microbiota-dependent metabolites, thus representing the possible biological substratum for the sarcopenia onset. In fact, the rearrangements of gut microbiota as well as the alteration of its functions contribute at increasing the anabolic resistance, releasing pro-inflammatory mediators, determining mitochondrial abnormalities with consequent oxidation, and causing insulin resistance. In this article, the link between gut microbiota and physical frailty is discussed. It is especially explained the role that sarcopenia may play in this likely bidirectional relationship.
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http://dx.doi.org/10.1016/j.exger.2019.110639DOI Listing
September 2019

Vitamin E and Alzheimer's disease: the mediating role of cellular aging.

Aging Clin Exp Res 2020 Mar 3;32(3):459-464. Epub 2019 May 3.

Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.

Background: Vitamin E represents a potent antioxidant and anti-inflammatory system, playing a role in Alzheimer's disease (AD). Different plasma concentrations of the forms of vitamin E are observed in AD compared to cognitively healthy subjects.

Aim: Since these modifications may modulate the markers of oxidative stress and cellular aging, we aim to explore the relationship between vitamin E forms and leukocyte telomere length (LTL) in AD.

Methods: 53 AD subjects and 40 cognitively healthy controls (CTs) were enrolled. The vitamin E forms (α-, β-, γ- and δ-tocopherol, α-, β-, γ- and δ-tocotrienol), the ratio of α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol (markers of oxidative/nitrosative damage) and LTL were measured.

Results And Discussion: Regression model was used to explore the associations of vitamin E forms and LTL with AD. The interaction of LTL in the association between vitamin E forms and AD was tested. AD subjects showed significantly lower concentrations of α-, β-, γ- and δ-tocopherol, α- and δ-tocotrienol, total tocopherols, total tocotrienols and total vitamin E compared to CTs. AD subjects showed higher values of nitrosative/oxidative damage. The adjusted analyses confirmed a significant relationship of AD with plasma concentrations of α- and β-tocopherols, δ-tocotrienol, total tocopherols, total tocotrienol, total vitamin E and oxidative/nitrosative damage. However, nitrosative damage was significantly associated with AD only in subjects with higher LTL and not in those expressing marked cellular aging.

Conclusions: Our study confirms the role of vitamin E in AD pathology and indicates that nitrosative damage influences the association with AD only in subjects characterized by longer LTL.
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http://dx.doi.org/10.1007/s40520-019-01209-3DOI Listing
March 2020

SNARE Complex Polymorphisms Associate with Alterations of Visual Selective Attention in Alzheimer's Disease.

J Alzheimers Dis 2019 ;69(1):179-188

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.

The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer's disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution in 192 AD, 187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: p = 1.5×10-4; MCI versus HC: p = 8.7×10-3) as well as A allele (AD versus HC: p = 6.0×10-4; MCI versus HC: p = 5.7×10-3) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (p = 0.032 and p = 0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (p = 0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pc = 0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pc = 0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas.
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http://dx.doi.org/10.3233/JAD-190147DOI Listing
September 2020

Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects.

Eur J Nutr 2020 Feb 16;59(1):119-126. Epub 2019 Jan 16.

Section of Gerontology and Geriatrics, Department of Medicine, Institute of Gerontology and Geriatrics, University of Perugia, Piazzale Gambuli 1, 06132, Perugia, Italy.

Purpose: Advancing age represents the strongest risk factor for Alzheimer's disease (AD), and the identification of biomarkers able to define what characterizes physiological aging from AD may represent a potential starting point for novel preventive strategies. Among these biomarkers, telomeres seem to be a promising target. Interestingly, high intake of carotenoid-rich food may play a role in protecting telomeres by oxidative stress reduction. Accordingly, low plasma β-carotene concentrations have been found in AD subjects when compared with cognitively healthy subjects. In this study, we aim at investigating the hypothesis that low β-carotene might be associated with markers of accelerated cellular aging, including leucocyte telomere length (LTL) and peripheral mononuclear cell (PBMC) telomerase activity in a cohort of old age subjects.

Methods: The study was conducted in 68 old age subjects, 37 AD, and 31 age-matched healthy controls. In all subjects, β-carotene plasma level, LTL and peripheral telomerase activity were measured.

Results: In all populations, β-carotene significantly and positively (r = 0.320, p = 0.008) correlated with telomerase activity, independent of gender. A model having telomerase activity levels as the dependent variable, and age, gender, smoking habit, and β-carotene as independent variables, confirmed that β-carotene was independently associated with telomerase activity (β = 0.319, p = 0.012). Subjects affected by AD had significantly lower plasmatic levels of β-carotene (448 ± 66 mg/ml vs 497 ± 59 mg/ml, p = 0.001) and LTL (0.53 ± 0.25 vs 0.69 ± 0.29; p = 0.009) as compared with healthy controls. Β-carotene plasma level was associated with AD diagnosis (OR 0.988; IC95% 0.978-0.997; p = 0.013) independently of age, gender, smoking habit, ApoE genotype, and LTL.

Conclusion: Our data show that β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates.
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http://dx.doi.org/10.1007/s00394-019-01892-yDOI Listing
February 2020

A case of right Alzheimer's disease.

Aging Clin Exp Res 2019 05 10;31(5):733-737. Epub 2019 Jan 10.

Geriatric Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Alfonso Lamarmora 5, 20122, Milan, Italy.

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http://dx.doi.org/10.1007/s40520-018-01116-zDOI Listing
May 2019